WT1mutations and single nucleotide polymorphism rs16754 analysis of patients with pediatric acute myeloid leukemia in a Chinese population

PurposeTo analyze the prevalence and clinical implications of Wilms' tumor 1 (WT1) single nucleotide polymorphism (SNP) rs16754 in the context of other prognostic markers in pediatric acute myeloid leukemia (AML).Patients and MethodsAvailable diagnostic marrow specimens (n = 790) from 1,328 patients enrolled in three consecutive Children's Cancer Group/Children's Oncology Group trials were analyzed for the presence of SNP rs16754. SNP status was correlated with disease characteristics, WT1 expression level, and clinical outcome.ResultsSNP rs16754 was present in 229 (29%) of 790 patients. The SNP was significantly more common in Asian and Hispanic patients and less common in white patients (P < .001). SNP rs16754 was also less common in patients with inv(16) (P = .043) and more common in patients with −5/del(5q) (P = .047). WT1 expression levels were significantly higher in patients with rs16754 or with WT1 mutations compared with WT1 wild-type patients (P = .021). Five-year overall survival (OS) for patients with and without the SNP was 60% and 50%, respectively (P = .031). Prognostic assessment by risk group demonstrated that in patients with low-risk disease, OS for those with and without SNP rs16754 was 90% versus 64% (P < .001) with a corresponding disease-free survival of 72% versus 53% (P = .041).ConclusionThe presence of SNP rs16754 was an independent predictor of improved OS; outcome differences were most pronounced in the low-risk subgroup. The high prevalence of WT1 SNP rs16754, and its correlation with improved outcome, identifies WT1 SNP rs16754 as a potentially important molecular marker of prognosis in pediatric AML.

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Genome-wide profiling of DNA copy number abnormalities in adult acute myeloid leukemia (AML) using high density single nucleotide polymorphism array

Journal of Clinical Oncology ◽

10.1200/jco.2008.26.15_suppl.7023 ◽

2008 ◽

Vol 26 (15_suppl) ◽

pp. 7023-7023

Author(s):

E. Ottaviani ◽

I. Iacobucci ◽

A. Astolfi ◽

F. Salmi ◽

N. Testoni ◽

...

Keyword(s):

Single Nucleotide Polymorphism ◽

Acute Myeloid Leukemia ◽

Copy Number ◽

Myeloid Leukemia ◽

Single Nucleotide Polymorphism Array ◽

High Density ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Genome Wide ◽

Acute Myeloid

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Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A

Blood ◽

10.1182/blood-2010-10-311019 ◽

2011 ◽

Vol 118 (14) ◽

pp. 3932-3941 ◽

Cited By ~ 215

Author(s):

Anna M. Jankowska ◽

Hideki Makishima ◽

Ramon V. Tiu ◽

Hadrian Szpurka ◽

Yun Huang ◽

...

Keyword(s):

Single Nucleotide Polymorphism ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Myelomonocytic Leukemia ◽

Molecular Heterogeneity ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Mutant Genotype ◽

Myelomonocytic Leukemia ◽

Acute Myeloid

Abstract Chronic myelomonocytic leukemia (CMML), a myelodysplastic/myeloproliferative neoplasm, is characterized by monocytic proliferation, dysplasia, and progression to acute myeloid leukemia. CMML has been associated with somatic mutations in diverse recently identified genes. We analyzed 72 well-characterized patients with CMML (N = 52) and CMML-derived acute myeloid leukemia (N = 20) for recurrent chromosomal abnormalities with the use of routine cytogenetics and single nucleotide polymorphism arrays along with comprehensive mutational screening. Cytogenetic aberrations were present in 46% of cases, whereas single nucleotide polymorphism array increased the diagnostic yield to 60%. At least 1 mutation was found in 86% of all cases; novel UTX, DNMT3A, and EZH2 mutations were found in 8%, 10%, and 5.5% of patients, respectively. TET2 mutations were present in 49%, ASXL1 in 43%, CBL in 14%, IDH1/2 in 4%, KRAS in 7%, NRAS in 4%, and JAK2 V617F in 1% of patients. Various mutant genotype combinations were observed, indicating molecular heterogeneity in CMML. Our results suggest that molecular defects affecting distinct pathways can lead to similar clinical phenotypes.

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Single Nucleotide Polymorphism in the Mutational Hotspot of WT1 Predicts a Favorable Outcome in Patients With Cytogenetically Normal Acute Myeloid Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2009.23.0342 ◽

2010 ◽

Vol 28 (4) ◽

pp. 578-585 ◽

Cited By ~ 96

Author(s):

Frederik Damm ◽

Michael Heuser ◽

Michael Morgan ◽

Haiyang Yun ◽

Anika Großhennig ◽

...

Keyword(s):

Single Nucleotide Polymorphism ◽

Acute Myeloid Leukemia ◽

Healthy Volunteers ◽

Myeloid Leukemia ◽

Minor Allele ◽

Risk Marker ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Risk Patients ◽

Acute Myeloid

Purpose We assessed the prognostic impact of a known single nucleotide polymorphism (SNP) located in the mutational hotspot of WT1 in patients with cytogenetically normal acute myeloid leukemia (CN-AML) in the context of other prognostic markers. Patients and Methods WT1 exons 7 and 9 from 249 CN-AML patients from multicenter treatment trials AML-SHG Hannover 0199 (Clinical Trials Identifier NCT00209833) and 0295, and 50 healthy volunteers were analyzed by direct sequencing. NPM1, FLT3, CEBPA, and MLL were assessed for mutations and WT1 expression was quantified. Results The minor allele of SNP rs16754 (WT1AG/GG) was found in 25.7% of CN-AML patients' blasts and germline DNA and in 36% of healthy volunteers. Patient characteristics, frequencies of mutations, or WT1 expression levels were similarly distributed between patients homozygous for the major allele compared with patients heterozygous or homozygous for the minor allele. SNP rs16754 status was an independent predictor of relapse-free survival (RFS; hazard ratio [HR], 0.49; 95% CI, 0.3 to 0.81; P = .005) and overall survival (OS; HR, 0.44; 95% CI, 0.27 to 0.74; P = .002) in multivariate analysis. The favorable effect of SNP rs16754 was stronger in NPM1/FLT3-ITD (internal tandem duplication of the FLT3 gene) high-risk patients compared with NPM1/FLT3-ITD low-risk patients. Favorable prognosis could not be identified by any other known low-risk marker in half the patients with at least one minor allele (13% of all patients). No difference for complete remission rate, RFS, or OS was found between patients with or without acquired WT1 mutations. Conclusion WT1 SNP rs16754 may be a novel independent favorable-risk marker in CN-AML patients that might improve risk and treatment stratification.

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